Confirmatory surgical exploration of the mediastinum after negative endobronchial ultrasound-guided transbronchial needle aspiration: which method and when to perform it, if needed

In patients with non-small cell lung cancer (NSCLC), minimally invasive endoscopy-based techniques [endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) with or without endoscopy ultrasound-fine needle aspiration (EUS-FNA)] are currently the recommended first choice for invasive mediastinal staging over surgical procedures (1-4). While it is accepted that an EBUS-TBNA procedure showing mediastinal metastases (N2 or N3 disease) is reliable enough given the low likelihood of a false positive result (5), the next step after a negative EBUS-TBNA result—performing a confirmatory surgical exploration of the mediastinum [video-assisted mediastinoscopy (VAM) or video-assisted mediastinoscopic lymphadenectomy (VAMLA)] or directly proceeding to a curative-intent treatment (surgical resection, radiotherapy, and ablation therapies)—is controversial (6). Current clinical guidelines for NSCLC mediastinal staging, which have not been updated in almost a decade, are not very clear in this regard. The American College of Chest Physicians recommends confirmatory mediastinoscopy in patients with abnormal mediastinum on positron emission tomography/computed tomography (PET/CT) (1). The European Society of Thoracic Surgeons (ESTS) recommends performing confirmatory mediastinoscopy except for patients with low or intermediate likelihood of N2 disease (normal mediastinum on PET/CT) after an EBUS-TBNA in which three or more stations {including both lower paratracheal [4L, 4R] and subcarinal [7]} were sampled (2). The European Society of Clinical Oncology, in a similar approach, recommends confirmatory mediastinoscopy in a situation of “high clinical suspicion” (3). Unfortunately, these definitions are not precisive in some cases. For instance, patients with normal mediastinum on PET/CT (a clinical situation that can be considered as low suspicion) and N1 involvement can have a rate of occult mediastinal disease up to 25–30% (7,8). Therefore, a more meticulous workup defining which situations require confirmatory mediastinoscopy is needed.

In 2019, Bousema et al. (9) published a meta-analysis describing the rate of occult unforeseen N2 disease (uN2) [considered as unexpected pathologic (p) N2 after surgical resection] in patients undergoing mediastinal staging through endoscopic techniques (endoscopy ultrasound and/or EBUS/TBNA) with or without confirmatory VAM. Surprisingly, the pooled rate of uN2 in the studies with EBUS-TBNA alone was lower (9.3%) than in the studies combining EBUS-TBNA with confirmatory VAM (11.1%). However, uN2 is a measure that depends not only on the diagnostic performance of EBUS-TBNA (and confirmatory VAM) but also on the prevalence of N2 disease in the studied population and on the thoroughness of the sampling during systematic nodal resection. In this setting, a recent meta-analysis (10) that measured the clinical value of confirmatory VAM showed that all published studies with confirmatory VAM included patients with both normal and abnormal mediastinum on PET/CT while some of the studies with only EBUS-TBNA included patients with only normal mediastinum on PET/CT and consequently, lower prevalence of occult N2. In this meta-analysis, the pooled sensitivity of confirmatory VAM after a negative EBUS-TBNA was of 66.9%, which is quite lower than that reported for VAM as a single staging method. These findings remark the fact that patients with a negative EBUS-TBNA are different from other patients without any previous staging procedure, and the following diagnostic VAM in such patients is more difficult than in “naïve” patients. Finally, the meta-analysis showed that the pooled number of patients needed to undergo a confirmatory VAM [number needed to treat (NNT)] to avoid a case of pN2 during resection was 23.8, and this rate was inversely related with the prevalence of N2 disease in the population. Following these two meta-analyses, and to clarify their contradictory results (in terms of uN2) the awaited MEDIASTrial (11), which is the only randomized controlled trial evaluating the usefulness of confirmatory VAM after negative EBUS-TBNA, has been recently published. The trial end point was noninferiority uN2 rate between two staging strategies: confirmatory VAM after EBUS-TBNA vs. direct surgical resection, considering a previously determined noninferiority difference set at 8%. The study included patients with proven or suspected NSCLC, an indication of invasive mediastinal staging (based on PET/CT) and a negative EBUS-TBNA (followed in 20% of cases by endoscopic ultrasonography by means of an EBUS scope). Three hundred and sixty patients underwent random assignment, 178 patients to the immediate lung tumor resection group (immediate resection group) and 182 to the confirmatory VAM group. After excluding dropouts of patients, the rate of uN2 was of 8.8% (15/171) in the immediate resection group and 7.7% (12/155) in the confirmatory VAM group. Based on these results, the authors suggested that after negative systematic EBUS-TBNA, confirmatory VAM can be omitted. However, this study had several limitations that must be considered. First, the primary end point of the study was uN2 which, as previously mentioned, not only depends on the sensitivity of the staging strategy (EBUS-TBNA alone vs. EBUS-TBNA plus confirmatory VAM) but also on the prevalence of N2 disease in both groups. In this setting, the prevalence of N2/3 disease in the immediate resection group [9.9% (17/171)] was lower than in the confirmatory VAM [16.0% (27/169)]. This finding could explain that, although confirmatory VAM diagnosed half of the patients with N2/3 disease in this group, the final rate of uN2 was similar between both groups. Second, confirmatory VAM diagnosed 14 out of 27 patients with N2/3 disease in the confirmatory VAM group, meaning a sensitivity of 51.8% for confirmatory VAM. This sensitivity is considerably lower than that previously reported for confirmatory VAM (66.9%) and can partially explain no differences in uN2 rate between both arms (10). Finally, the benefits of omitting confirmatory VAM are reducing costs, morbidity, mortality and reducing delays to surgery. Actually, in the MEDIASTrial there were reductions in morbidity and mortality in the immediate resection group (although these differences were not statistically significant due to the sample size) but the differences in the interval between EBUS-TBNA and surgical resection was 10 days between groups which is probably not clinically relevant for the outcomes of the patients.

Interestingly, in the MEDIASTrial, the bigger differences in uN2 rate between immediate resection group and confirmatory VAM were found in patients with cN1 disease which represents a clinical situation were EBUS-TBNA achieves a very low diagnostic performance. Only two studies have analyzed the usefulness of EBUS-TBNA in this clinical situation (7,8) and both have shown a low sensitivity (38% and 40% respectively). In one of these studies (7), patients with negative EBUS-TBNA underwent confirmatory VAM that doubled the sensitivity of EBUS-TBNA alone from 38% to 73%. More studies are needed to clarify which situations can benefit from confirmatory VAM or not. Unfortunately, with the results of the MEDIASTrial no recommendations of each specific scenario can be made.

In conclusion, the likelihood of occult mediastinal disease after a negative EBUS-TBNA depends on the performance of the procedure and the prevalence of N2, that depends on the mediastinal appearance on PET/CT, tumor size and location. Following the results of the MEDIASTrial, the benefit of adding a confirmatory VAM after a negative EBUS seems sparse. The role of confirmatory transcervical lymphadenectomies after a negative EBUS-TBNA has been barely investigated (12,13), but could be helpful, especially in patients with normal mediastinum by PET/CT and high suspicion of N2, such as patients with cN1 on PET/CT, where the uN2 rate identified by VAMLA can be as high as 40% (14). VAMLA and transcervical extended mediastinal lymphadenectomy (TEMLA), in addition of being more accurate than mediastinoscopy, can also be viewed as the first therapeutic step to avoid mediastinal lymphadenectomy at the time of surgical resection. Finally, novel studies showing good results of induction therapy with immunotherapy in patients with N1/2 disease (15,16) must encourage clinicians involved in the work-up of patients with NSCLC to find the better strategies to detect nodal disease before surgery.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-23-46/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-23-46/coif). J.S.S. has received grant from the Spanish society of pulmonology (SEPAR) and payment from Astra Zeneca and Zambom for two lectures. Additionally, Sanofi payed his inscription to the ATS Congress in 2023. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Silvestri GA, Gonzalez AV, Jantz MA, et al. Methods for staging non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143:e211S-50S.
2. De Leyn P, Dooms C, Kuzdzal J, et al. Revised ESTS guidelines for preoperative mediastinal lymph node staging for non-small-cell lung cancer. Eur J Cardiothorac Surg 2014;45:787-98. [Crossref] [PubMed]
3. Postmus PE, Kerr KM, Oudkerk M, et al. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017;28:iv1-iv21. [Crossref] [PubMed]
4. Annema JT, van Meerbeeck JP, Rintoul RC, et al. Mediastinoscopy vs endosonography for mediastinal nodal staging of lung cancer: a randomized trial. JAMA 2010;304:2245-52. [Crossref] [PubMed]
5. Sanz-Santos J, Andreo F, Serra P, et al. False positive endobronchial ultrasound-guided real-time transbronchial needle aspiration secondary to bronchial carcinoma in situ at the point of puncture: a case report. J Cardiothorac Surg 2012;7:74. [Crossref] [PubMed]
6. Sanz-Santos J, Call S. Preoperative staging of the mediastinum is an essential and multidisciplinary task. Respirology 2020;25:37-48. [Crossref] [PubMed]
7. Dooms C, Tournoy KG, Schuurbiers O, et al. Endosonography for mediastinal nodal staging of clinical N1 non-small cell lung cancer: a prospective multicenter study. Chest 2015;147:209-15. [Crossref] [PubMed]
8. Kim BG, Cho JH, Shin SH, et al. Diagnostic Performance of Endosonography to Detect Mediastinal Lymph Node Metastasis in Patients with Radiological N1 Non-Small Cell Lung Cancer. Cancer Res Treat 2023;55:832-40. [Crossref] [PubMed]
9. Bousema JE, van Dorp M, Noyez VJJM, et al. Unforeseen N2 Disease after Negative Endosonography Findings with or without Confirmatory Mediastinoscopy in Resectable Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis. J Thorac Oncol 2019;14:979-92. [Crossref] [PubMed]
10. Sanz-Santos J, Almagro P, Malik K, et al. Confirmatory Mediastinoscopy after Negative Endobronchial Ultrasound-guided Transbronchial Needle Aspiration for Mediastinal Staging of Lung Cancer: Systematic Review and Meta-analysis. Ann Am Thorac Soc 2022;19:1581-90. [Crossref] [PubMed]
11. Bousema JE, Dijkgraaf MGW, van der Heijden EHFM, et al. Endosonography With or Without Confirmatory Mediastinoscopy for Resectable Lung Cancer: A Randomized Clinical Trial. J Clin Oncol 2023;41:3805-15. [Crossref] [PubMed]
12. Zielinski M, Szlubowski A, Kołodziej M, et al. Comparison of endobronchial ultrasound and/or endoesophageal ultrasound with transcervical extended mediastinal lymphadenectomy for staging and restaging of non-small-cell lung cancer. J Thorac Oncol 2013;8:630-6. [Crossref] [PubMed]
13. Szlubowski A, Herth FJ, Soja J, et al. Endobronchial ultrasound-guided needle aspiration in non-small-cell lung cancer restaging verified by the transcervical bilateral extended mediastinal lymphadenectomy--a prospective study. Eur J Cardiothorac Surg 2010;37:1180-4. [Crossref] [PubMed]
14. Call S, Obiols C, Rami-Porta R, et al. Video-Assisted Mediastinoscopic Lymphadenectomy for Staging Non-Small Cell Lung Cancer. Ann Thorac Surg 2016;101:1326-33. [Crossref] [PubMed]
15. Forde PM, Spicer J, Lu S, et al. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med 2022;386:1973-85. [Crossref] [PubMed]
16. Provencio M, Serna-Blasco R, Nadal E, et al. Overall Survival and Biomarker Analysis of Neoadjuvant Nivolumab Plus Chemotherapy in Operable Stage IIIA Non-Small-Cell Lung Cancer (NADIM phase II trial). J Clin Oncol 2022;40:2924-33. [Crossref] [PubMed]